One of the most important features in all normal subjects is that they do not harmfully react against antigenic materials forming a self while they are capable of recognizing, reacting to, and removing numerous non-self antigens. The above biological phenomenon of not being responsive to self antigens is called immunologic unresponsiveness or tolerance. Self-tolerance occurs when the lymphocytes which may have specific receptors for self antigens are removed or when the reactive function that responds to self antigens after being contacted is inactivated. When there is a problem in inducing or maintaining self-tolerance an immune response occurs against self antigens, and the diseases caused thereby is called an autoimmune disease.
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease in the central nervous system affecting more than a million people worldwide. MS causes substantial disorders due to deficiency in sensation and locomotion, autonomy and neurocognitive functions. The mechanism of developing the disease generally appears to be an autoimmune pathology in which CD4+ T helper 1 cells (Th1: IFN-γ producing CD4+ T cells), T helper 17 cells (Th17: IL-17A producing CD4+ T cells) and regulatory T cells (Treg) play important roles. Many clinical and pathological characteristics of the experimental autoimmune encephalomyelitis (EAE), which is an animal model of human MS, show proximal similarity to that of MS. Accordingly, EAE has been generally used as an experimental model system for studying the mechanism of MS development and for testing the efficacy of potential therapeutic agents for MS. Therapeutic agents for controlling diseases such as IFN-β and glatiramer acetate have been widely used for MS treatment, showing advantageous effects. However, due to limitations on therapeutic methods many MS patients have been looking for selective alternative therapies. Allegedly, about 50% to 75% of MS patients are using at least one complementary and alternative medicinal therapy.
An allergic disease refers to a disease caused by a disorder in immune system in which a substance non-harmful to normal people causes hypersensitivities with various symptoms to particular people. A substance that causes an allergic disease is called an allergen or antigen, and pollens, antibiotics, drugs, dusts, foods, cold air, sunlight, etc., may causes the allergies. The symptoms of the allergic diseases include hives, sneezing, pruritus, rhinorrhea, coughs, hay fever, ocular hyperemia, eczema, rashes, etc. Representative allergic diseases are allergic asthma, which accompany symptoms such as airway constriction, increase in the secretion of mucus liquid in the lungs, dyspnea, and coughs, and additionally may include atopic dermatitis, conjunctivitis, rhinitis, and ulcerative colitis.
Neurodegenerative diseases are associated with symptoms such as degeneration, loss of functions, and often apoptosis of neurons. Since these symptoms are progressive they are often highly destructive unlike the neurodegenerative diseases. Patients with neurodegenerative diseases may experience extreme deterioration in their cognitive or motor performance. Accordingly, the quality of their lives and expectation thereto may be considerably deteriorated.
Parkinson's disease (PD) is a representative progressive neurodegenerative disease characterized by loss of dopaminergic (DA) neurons in substantia nigra (SN), and shaking, rigidity, slowness of movement, and bradykinesia due to decrease in dopamine in striatum (STR). PD is a sporadic disease whose pathogenesis has not been identified. According to the evidence accumulated so far, neuroinflammation appears to play an important role in the pathogenesis of PD. The primary trigger of neuroinflammation is activated microglia, which are innate immune cells of the central nervous system (CNS) discovered in degenerative DA neurons and therearound. Microglia are dramatically activated by responding to neuronal damage, and ROS and/or produce various potential neurotoxins including proinflammatory cytokines. Until recently, the role of the adoptive immune system has been increasingly emphasized in PD pathogenesis. Examples of therapeutic drugs for treating PD include L-dopa preparation, dopamine agonists, anticholinergics, Eldepryl (depreyl), etc. Most of these drugs are involved in regulating the symptoms of PD rather than treating its cause, and thus they should be administered continuously without cessation. However, long-term administration of these drugs may lead to drug intoxication. For example, anticholinergics may cause disorders in autonomic nervous system or abnormalities in mental functions and thus its long-term administration to people of senile age are limited. Additionally, the efficacies of L-dopa preparations may progressively deteriorate as the duration of its administration becomes long, and may also incur adverse effects such as twisting of the body and involuntary movements of hands or legs. Accordingly, in order to prevent the adverse effects, active efforts have been made to develop a therapeutic agent derived from natural substances for PD treatment. For example, pharmaceutical compositions containing a Scutellariae Radix extract (KR Patent Application Publication No. 2001-0081188), a Beauveria Bassiana 101A extract (KR Patent Application Publication No. 2004-0012396), a peach leaf extract (KR Patent Application Publication No. 2010-0060949), etc., as active ingredients have been disclosed. Although the components derived from natural substances have no adverse effects they are disadvantageous due to low therapeutic effects for PD treatment.
Since the introduction of the regulatory T cell concept on early 1970s by Gershon based on the possibility of the presence of T cells capable of controlling and inhibiting the effector functions of palliative T cells (conventional T cells), and its first disclosure (R. K. Gershon and K. Kondo, Immunology, 1970, 18: 723-37), studies have been focused on the elucidation of biological characteristics and functions of regulatory cells in many fields of immunology.
In particular, since Sakaguchi suggested in 1995 that CD25 can act as an important phenotypic marker for naturally-occurring CD4+ regulatory T cells (S. Sakaguchi et al., J. Immunol., 1995, 155: 1151-1164), the studies have focused on the roles and importance of regulatory T cells in inducing peripheral tolerance regarding self antigens.
Bee venom is an alternative medicine widely used for the treatment of a few immune diseases, in particular rheumatoid arthritis. The existing studies have disclosed that bee venom treatment can alleviate rheumatoid arthritis and has an anti-inflammatory effect in humans and experimental animals. Additionally, although there are evidence-based descriptive reports on the alleged improvement of neuropathy symptoms by MS patients who have received multiple repeated bee venom acupunctures a conclusive decision on the bee venom efficacy has not been made due to lack of detailed studies, and currently there is almost no evidence supporting the use of bee venom in MS treatment.
Meanwhile, although bee venom is widely used as an alternative medicine, considering the risk of hypersensitivity, shock response, etc., in using bee venom, it is necessary to identify specific active ingredients and the working mechanism of bee venom, and to use it as a more purified drug.